臺灣博碩士論文加值系統

A群鏈球菌會引起感染後併發症，例如急性腎絲球腎炎與風濕性心臟病。而引發這種後遺症的原因被認為是A群鏈球菌的分子與宿主的抗原有分子上相似的現象，稱為molecular mimicry。鏈球菌熱原性外毒素B(SPE B)是一種cysteine protease，是A群鏈球菌主要的細胞外蛋白質，先前的研究顯示在A群鏈球菌中腎炎型菌株(nephritic strain)與其他型非腎炎型菌株比較，會分泌較大量的SPE B，因此SPE B也被認為是腎原性抗原(nephritogenic antigen)，可能參與急性腎絲球腎炎的致病機轉。在本論文中，我們利用動物模式以主動免疫小鼠SPE B與被動免疫給予anti-SPE B抗體兩種方式，證實anti-SPE B抗體在急性腎絲球腎炎致病機轉的角色，實驗結果顯示主動免疫小鼠SPE B其腎臟會有病變與蛋白尿的情形。而在主動免疫SPE A或小牛血清蛋白(BSA)的小鼠腎臟則沒有明顯的組織病變。主動免疫SPE B小鼠的腎臟絲球體發現有免疫球蛋白沉積、補體活化與白血球浸潤。Anti-SPE B單株抗體10G與腎臟的內皮細胞有交叉反應(cross-reactivity)，並且造成小鼠腎臟損傷與蛋白尿的發生。除此之外，單株抗體10G也會與心臟的內皮細胞有交叉作用，包括人類的瓣膜內皮細胞與小鼠的心臟內皮細胞。先前的研究報導指出，風濕性心臟病的初期是由自體抗體造成瓣膜的內皮細胞發炎，進而吸引T細胞浸潤最終導致心臟組織的損傷。因此我們利用peptide array與合成片段胜肽的ELISA確定單株抗體10G所辨識SPE B的抗原決定位(antigenic epitope)。結果顯示單株抗體10G辨識的主要抗原決定位為SPE B胺基酸296-310的位置，並且單株抗體10G與內皮細胞株HMEC-1的交叉反應會被SPE B胺基酸 296-310的合成胜肽所抑制。在風溼性心臟病病人血清的研究發現，anti-SPE B抗體IgG的量較高，並且與病人血清交叉反應到內皮細胞株HMEC-1的程度呈現顯著的正相關，病人血清與內皮細胞的交叉反應亦可以被SPE B胺基酸 296-310的合成胜肽所抑制。總結而言，本篇論文發現(1)主動免疫小鼠SPE B與直接被動免疫給予anti-SPE B抗體都會造成小鼠腎臟病變，(2)anti-SPE B抗體可能藉由與腎臟絲球體的內皮細胞有交叉反應而參與了急性腎絲球腎炎的致病機轉，(3)anti-SPE B抗體亦可能參與了風濕性心臟病的致病機轉，而主要的SPE B抗原決定位為SPE B胺基酸296-310。

Group A streptococcal infection may cause post-infectious sequelae, such as acute post-streptococcal glomerulonephritis (APSGN) and rheumatic heart disease (RHD). Molecular mimicry between group A streptococcus and host antigens is thought to play roles in the development of post-streptococcal sequelae. Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is a predominant extracellular protein. Previous studies showed that nephritis-associated strains preferentially secreted SPE B compared to non-nephritis-associated strains. Zymogen/SPE B was proposed as the major nephritogenic antigen involved in the pathogenesis of APSGN. Using a mouse model, we demonstrated the pathologic role of anti-SPE B antibody in the pathogenesis of glomerulonephritis. Mice were actively immunized with recombinant SPE B or passively immunized with anti-SPE B antibody. Mice immunized with SPE B showed pathologic changes in kidney and proteinuria. None of the mice given bovine serum albumin or SPE A showed any marked change in renal tissue. Immunoglobulin deposition, complement activation, and cell infiltration occurred only in the glomeruli of SPE B-hyperimmunized mice. One monoclonal anti-SPE B antibody clone, 10G, was cross-reactive with kidney endothelial cells. Furthermore, monoclonal antibody 10G caused kidney injury and proteinuria in mice. Besides the binding with glomerular endothelial cells, monoclonal antibody 10G could also cross-react with human heart valve and mouse heart endothelial cells. Previous studies have reported that autoantibodies caused valve endothelial inflammation, followed by T cell infiltration and heart tissue damage in RHD. Therefore, we conducted peptide array and ELISA using synthetic peptides to identify SPE B antigenic epitopes recognized by 10G. Results showed that the major epitope of monoclonal antibody 10G is localized in amino acid 296-310 residues of SPE B. The cross-reactivity of 10G with endothelial cells was inhibited by pre-absorption with SPE B amino acids 296-310 peptides. Studies with patient sera indicated that the levels of anti-SPE B immunoglobulin G (IgG) and the endothelial cell binding activity of RHD patient sera were significantly higher than control sera. The levels of anti-SPE B IgG in RHD patient sera were positively correlated with the endothelial cell binding activity. Furthermore, the binding activities to SPE B and to endothelial cells of RHD patient sera were reduced by pre-absorption with SPE B amino acids 296-310 peptides. In conclusion, we found that (1) both SPE B hyperimmunization and passive immunization with anti-SPE B antibody caused pathologic changes in mouse kidneys, (2) anti-SPE B antibodies cross-reacted with glomerular endothelial cells, which may be involved in the pathogenesis of APSGN after group A streptococcal infection, (3) anti-SPE B antibodies, at least in part, play roles in the pathogenesis of RHD, and the amino acid residues 296-310 of SPE B possess a dominant epitope.

Chinese Abstract．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．I
English Abstract．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．III
致謝．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．V
Contents．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．VI
Index of Tables．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．IX
Index of Figures．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．X
Abbreviations．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．XII
Introduction．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．1
Specific Aims．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．9
Materials and Methods．．．．．．．．．．．．．．．．．．．．．．．．．．．．．10
I. Materials．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．10
I-1. Preparing recombinant SPE B and its mutant C192S．．．．．．．．．．10
I-2. Mice．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．10
I-3. Generating monoclonal anti-SPE B antibody．．．．．．．．．．．．．11
I-4. Cell culture．．．．．．．．．．．．．．．．．．．．．．．．．．．．．11
I-5. Patient sera and heart valve specimens．．．．．．．．．．．．．．．．11
I-6. Synthetic peptides．．．．．．．．．．．．．．．．．．．．．．．．．．12
II. Methods．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．13
II-1. Immunization protocol．．．．．．．．．．．．．．．．．．．．．．．13
II-2. Histopathology．．．．．．．．．．．．．．．．．．．．．．．．．．．13
II-3. Immunohistochemistry staining．．．．．．．．．．．．．．．．．．．13
II-4. Proteinuria assay．．．．．．．．．．．．．．．．．．．．．．．．．．15
II-5. Extracting endothelial cell membrane proteins．．．．．．．．．．．．16
II-6. Two-dimensional gel electrophoresis．．．．．．．．．．．．．．．．．16
II-7. Silver staining．．．．．．．．．．．．．．．．．．．．．．．．．．．17
II-8. Western blotting．．．．．．．．．．．．．．．．．．．．．．．．．．．18
II-9. Spot analysis and mass spectrometry．．．．．．．．．．．．．．．．．18
II-10. Flow cytometry．．．．．．．．．．．．．．．．．．．．．．．．．．19
II-11. ELISA．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．19
II-12. Phage display peptide library．．．．．．．．．．．．．．．．．．．．21
II-13. Peptide array．．．．．．．．．．．．．．．．．．．．．．．．．．．21
II-14. Peptide pre-absorption．．．．．．．．．．．．．．．．．．．．．．．22
II-15. Statistical analysis．．．．．．．．．．．．．．．．．．．．．．．．．22
Results．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．23
I. Role of anti-SPE B antibodies in APSGN．．．．．．．．．．．．．．．．．．23
I-1. Pathologic changes in the kidneys of SPE B-hyperimmunized mice．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．23
I-2. Immunoglobulin deposition, complement activation, and leukocyte infiltration in mouse kidney glomeruli．．．．．．．．．．．．．．．．．23
I-3. Urinary protein levels in SPE B-hyperimmunized mice．．．．．．．．24
I-4. Monoclonal anti-SPE B antibody 10G binds to mouse glomerular endothelial cells and causes kidney injury and proteinuria．．．．．．．25
I-5. Endothelial cell membrane proteins recognized by anti-SPE B antibody．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．25
II. Role of anti-SPE B antibodies in RHD．．．．．．．．．．．．．．．．．．．25
II-1. Anti-SPE B mAb 10G binds to human heart valve and mouse
endothelial cells．．．．．．．．．．．．．．．．．．．．．．．．．．．26
II-2. Identification of epitope recognized by anti-SPE B mAb 10G．．．．．27
II-3. Anti-SPE B antibody levels in RHD patient sera are higher than in control sera and are positively correlated with endothelial cell binding activity．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．28
II-4. The SPE B-and endothelial cell-binding activities of RHD patient sera are reduced by P7-8 peptide pre-absorption．．．．．．．．．．．．．．．29
Discussion．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．30
References．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．41
Tables．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．55
Figures．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．59
Appendix．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．．81

Ades, E.W., Candal, F.J., Swerlick, R.A., George, V.G., Summers, S., Bosse, D.C. & Lawley, T.J. (1992) HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol, 99, 683-690.
Ahn, S.Y. & Ingulli, E. (2008) Acute poststreptococcal glomerulonephritis: an update. Curr Opin Pediatr, 20, 157-162.
Arner, E.S. & Holmgren, A. (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem, 267, 6102-6109.
Asea, A., Kraeft, S.K., Kurt-Jones, E.A., Stevenson, M.A., Chen, L.B., Finberg, R.W., Koo, G.C. & Calderwood, S.K. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med, 6, 435-442.
Batsford, S.R., Mezzano, S., Mihatsch, M., Schiltz, E. & Rodriguez-Iturbe, B. (2005) Is the nephritogenic antigen in post-streptococcal glomerulonephritis pyrogenic exotoxin B (SPE B) or GAPDH? Kidney Int, 68, 1120-1129.
Bertini, R., Howard, O.M., Dong, H.F., Oppenheim, J.J., Bizzarri, C., Sergi, R., Caselli, G., Pagliei, S., Romines, B., Wilshire, J.A., Mengozzi, M., Nakamura, H., Yodoi, J., Pekkari, K., Gurunath, R., Holmgren, A., Herzenberg, L.A., Herzenberg, L.A. & Ghezzi, P. (1999) Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells. J Exp Med, 189, 1783-1789.
Besbas, N., Ozaltin, F., Catal, F., Ozen, S., Topaloglu, R. & Bakkaloglu, A. (2004) Monocyte chemoattractant protein-1 and interleukin-8 levels in children with acute poststreptococcal glomerulonephritis. Pediatr Nephrol, 19, 864-868.
Bisno, A.L. (1990) The resurgence of acute rheumatic fever in the United States. Annu Rev Med, 41, 319-329.
Bisno, A.L. (1991) Group A streptococcal infections and acute rheumatic fever. N Engl J Med, 325, 783-793.
Bisno, A.L., Brito, M.O. & Collins, C.M. (2003) Molecular basis of group A streptococcal virulence. Lancet Infect Dis, 3, 191-200.
Bronze, M.S., Beachey, E.H. & Dale, J.B. (1988) Protective and heart-cross-reactive epitopes located within the NH2 terminus of type 19 streptococcal M protein. J Exp Med, 167, 1849-1859.
Carapetis, J.R. (2007) Rheumatic heart disease in developing countries. N Engl J Med, 357, 439-441.
Carapetis, J.R., McDonald, M. & Wilson, N.J. (2005a) Acute rheumatic fever. Lancet, 366, 155-168.
Carapetis, J.R., Steer, A.C., Mulholland, E.K. & Weber, M. (2005b) The global burden of group A streptococcal diseases. Lancet Infect Dis, 5, 685-694.
Chen, C.Y., Luo, S.C., Kuo, C.F., Lin, Y.S., Wu, J.J., Lin, M.T., Liu, C.C., Jeng, W.Y. & Chuang, W.J. (2003) Maturation processing and characterization of streptopain. J Biol Chem, 278, 17336-17343.
Cu, G.A., Mezzano, S., Bannan, J.D. & Zabriskie, J.B. (1998) Immunohistochemical and serological evidence for the role of streptococcal proteinase in acute post-streptococcal glomerulonephritis. Kidney Int, 54, 819-826.
Cunningham, M.W. (2000) Pathogenesis of group A streptococcal infections. Clin Microbiol Rev, 13, 470-511.
Cunningham, M.W. (2003) Autoimmunity and molecular mimicry in the pathogenesis of post-streptococcal heart disease. Front Biosci, 8, s533-543.
Cunningham, M.W. (2004) T cell mimicry in inflammatory heart disease. Mol Immunol, 40, 1121-1127.
Cunningham, M.W., Antone, S.M., Smart, M., Liu, R. & Kosanke, S. (1997) Molecular analysis of human cardiac myosin-cross-reactive B- and T-cell epitopes of the group A streptococcal M5 protein. Infect Immun, 65, 3913-3923.
Cunningham, M.W., McCormack, J.M., Fenderson, P.G., Ho, M.K., Beachey, E.H. & Dale, J.B. (1989) Human and murine antibodies cross-reactive with streptococcal M protein and myosin recognize the sequence GLN-LYS-SER-LYS-GLN in M protein. J Immunol, 143, 2677-2683.
Cunningham, M.W., Hall, N.K., Krisher, K.K. & Spanier, A.M. (1986) A study of anti-group A streptococcal monoclonal antibodies cross-reactive with myosin. J Immunol, 136, 293-298.
Cunningham, M.W., McCormack, J.M., Talaber, L.R., Harley, J.B., Ayoub, E.M., Muneer, R.S., Chun, L.T. & Reddy, D.V. (1988) Human monoclonal antibodies reactive with antigens of the group A Streptococcus and human heart. J Immunol, 141, 2760-2766.
Cunningham, M.W. & Swerlick, R.A. (1986) Polyspecificity of antistreptococcal murine monoclonal antibodies and their implications in autoimmunity. J Exp Med, 164, 998-1012.
Currie, B.J. (2006) Group A streptococcal infections of the skin: molecular advances but limited therapeutic progress. Curr Opin Infect Dis, 19, 132-138.
da Silva, C.H. (1999) Rheumatic fever: a multicenter study in the state of Sao Paulo. Pediatric Committee--Sao Paulo Pediatric Rheumatology Society. Rev Hosp Clin Fac Med Sao Paulo, 54, 85-90.
Ellis, N.M., Li, Y., Hildebrand, W., Fischetti, V.A. & Cunningham, M.W. (2005) T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease. J Immunol, 175, 5448-5456.
Fae, K.C., da Silva, D.D., Oshiro, S.E., Tanaka, A.C., Pomerantzeff, P.M., Douay, C., Charron, D., Toubert, A., Cunningham, M.W., Kalil, J. & Guilherme, L. (2006) Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol, 176, 5662-5670.
Fenderson, P.G., Fischetti, V.A. & Cunningham, M.W. (1989) Tropomyosin shares immunologic epitopes with group A streptococcal M proteins. J Immunol, 142, 2475-2481.
Frank, R. (2002) The SPOT-synthesis technique. Synthetic peptide arrays on membrane supports--principles and applications. J Immunol Methods, 267, 13-26.
Galvin, J.E., Hemric, M.E., Ward, K. & Cunningham, M.W. (2000) Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. J Clin Invest, 106, 217-224.
Giannessi, D., Colotti, C., Maltinti, M., Del Ry, S., Prontera, C., Turchi, S., Labbate, A. & Neglia, D. (2007) Circulating heat shock proteins and inflammatory markers in patients with idiopathic left ventricular dysfunction: their relationships with myocardial and microvascular impairment. Cell Stress Chaperones, 12, 265-274.
Goroncy-Bermes, P., Dale, J.B., Beachey, E.H. & Opferkuch, W. (1987) Monoclonal antibody to human renal glomeruli cross-reacts with streptococcal M protein. Infect Immun, 55, 2416-2419.
Graham, M.R., Smoot, L.M., Lei, B. & Musser, J.M. (2001) Toward a genome-scale understanding of group A Streptococcus pathogenesis. Curr Opin Microbiol, 4, 65-70.
Guilherme, L., Fae, K., Oshiro, S.E. & Kalil, J. (2005) Molecular pathogenesis of rheumatic fever and rheumatic heart disease. Expert Rev Mol Med, 7, 1-15.
Guilherme, L., Kalil, J. & Cunningham, M. (2006) Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity, 39, 31-39.
Gulizia, J.M., Cunningham, M.W. & McManus, B.M. (1991) Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes. Am J Pathol, 138, 285-301.
Hytonen, J., Haataja, S., Gerlach, D., Podbielski, A. & Finne, J. (2001) The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity. Mol Microbiol, 39, 512-519.
Jikimoto, T., Nishikubo, Y., Koshiba, M., Kanagawa, S., Morinobu, S., Morinobu, A., Saura, R., Mizuno, K., Kondo, S., Toyokuni, S., Nakamura, H., Yodoi, J. & Kumagai, S. (2002) Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis. Molecular Immunology, 38, 765-772.
Jimenez, A., Zu, W., Rawe, V.Y., Pelto-Huikko, M., Flickinger, C.J., Sutovsky, P., Gustafsson, J.A., Oko, R. & Miranda-Vizuete, A. (2004) Spermatocyte/spermatid-specific thioredoxin-3, a novel Golgi apparatus-associated thioredoxin, is a specific marker of aberrant spermatogenesis. J Biol Chem, 279, 34971-34982.
Jordan, P. & Kubler, D. (1995) Autoimmune diseases: nuclear autoantigens can be found at the cell-surface. Mol Biol Rep, 22, 63-66.
Kaplan, E.L. (2005) Pathogenesis of acute rheumatic fever and rheumatic heart disease: evasive after half a century of clinical, epidemiological, and laboratory investigation. Heart, 91, 3-4.
Kaplan, M.H., Bolande, R., Rakita, L. & Blair, J. (1964) Presence of bound immunoglobulins and complement in the myocardium in acute rheumatic fever. Association with cardiac failure. N Engl J Med, 271, 637-645.
Kaplan, M.H. & Meyeserian, M. (1962) An immunological cross-reaction between group-A streptococcal cells and human heart tissue. Lancet, 1, 706-710.
Kaplan, M.H. & Suchy, M.L. (1964) Immunologic relation of streptococcal and tissue antigens. Ii. Cross-reaction of antisera to mammalian heart tissue with a cell wall constituent of certain strains of group A Streptococci. J Exp Med, 119, 643-650.
Kaplan, M.H. & Svec, K.H. (1964) Immunologic relation of streptococcal and tissue antigens. Iii. Presence in human sera of streptococcal antibody cross-reactive with heart tissue. Association with streptococcal infection, rheumatic fever, and glomerulonephritis. J Exp Med, 119, 651-666.
Kirvan, C.A., Swedo, S.E., Heuser, J.S. & Cunningham, M.W. (2003) Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med, 9, 914-920.
Kudat, H., Telci, G., Sozen, A.B., Oguz, F., Akkaya, V., Ozcan, M., Atilgan, D., Carin, M. & Guven, O. (2006) The role of HLA molecules in susceptibility to chronic rheumatic heart disease. Int J Immunogenet, 33, 41-44.
Kuo, C.F., Luo, Y.H., Lin, H.Y., Huang, K.J., Wu, J.J., Lei, H.Y., Lin, M.T., Chuang, W.J., Liu, C.C., Jin, Y.T. & Lin, Y.S. (2004) Histopathologic changes in kidney and liver correlate with streptococcal pyrogenic exotoxin B production in the mouse model of group A streptococcal infection. Microb Pathog, 36, 273-285.
Kuo, C.F., Wu, J.J., Lin, K.Y., Tsai, P.J., Lee, S.C., Jin, Y.T., Lei, H.Y. & Lin, Y.S. (1998) Role of streptococcal pyrogenic exotoxin B in the mouse model of group A streptococcal infection. Infect Immun, 66, 3931-3935.
Kuo, C.F., Wu, J.J., Tsai, P.J., Kao, F.J., Lei, H.Y., Lin, M.T. & Lin, Y.S. (1999) Streptococcal pyrogenic exotoxin B induces apoptosis and reduces phagocytic activity in U937 cells. Infect Immun, 67, 126-130.
Kurahara, D., Tokuda, A., Grandinetti, A., Najita, J., Ho, C., Yamamoto, K., Reddy, D.V., Macpherson, K., Iwamuro, M. & Yamaga, K. (2002) Ethnic differences in risk for pediatric rheumatic illness in a culturally diverse population. J Rheumatol, 29, 379-383.
Layrisse, Z., Rodriguez-Iturbe, B., Garcia-Ramirez, R., Rodriguez, A. & Tiwari, J. (1983) Family studies of the HLA system in acute poststreptococcal glomerulonephritis. Hum Immunol, 7, 177–185.
Li, Y., Heuser, J.S., Cunningham, L.C., Kosanke, S.D. & Cunningham, M.W. (2006) Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol, 177, 8234-8240.
Malpas, J. S. & Landon, J. (1960) Rheumatic fever in the young adult. Ann Rheum Dis, 19, 262-267.
Manjula, B.N., Trus, B.L. & Fischetti, V.A. (1985) Presence of two distinct regions in the coiled-coil structure of the streptococcal Pep M5 protein: relationship to mammalian coiled-coil proteins and implications to its biological properties. Proc Natl Acad Sci USA, 82, 1064-1068.
Mccarty, M. (1956) Variation in the group-specific carbohydrate of group A streptococci. II. Studies on the chemical basis for serological specificity of the carbohydrates. J Exp Med, 104, 629-643.
Malkiel, S., Liao, L., Cunningham, M.W. & Diamond, B. (2000) T-cell-dependent antibody response to the dominant epitope of streptococcal polysaccharide, N-acetyl-glucosamine, is cross-reactive with cardiac myosin. Infect Immun, 68, 5803-5808.
Marijon, E., Ou, P., Celermajer, D.S., Ferreira, B., Mocumbi, A.O., Jani, D., Paquet, C., Jacob, S., Sidi, D. & Jouven, X. (2007) Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med, 357, 470-476.
Martins, T.B., Veasy, L.G. & Hill, H.R. (2006) Antibody responses to group A streptococcal infections in acute rheumatic fever. Pediatr Infect Dis J, 25, 832-837.
Matsell, D.G., Baldree, L.A., DiSessa, T.G., Gaber, L.S. & Stapleton, F.B. (1990) Acute poststreptococcal glomerulonephritis and acute rheumatic fever: occurrence in the same patient. Child Nephrol Urol, 10, 112-114.
McDonald, M., Currie, B.J. & Carapetis, J.R. (2004) Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis, 4, 240-245.
McIntosh, R.M., Garcia, R., Rubio, L., Rabideau, D., Allen, J.E., Carr, R.I. & Rodriguez-Iturbe, B. (1978) Evidence of an autologous immune complex pathogenic mechanism in acute poststreptococcal glomerulonephritis. Kidney Int, 14, 501-510.
Nakamura, H., De Rosa, S., Roederer, M., Anderson, M.T., Dubs, J.G., Yodoi, J., Holmgren, A., Herzenberg, L.A. & Herzenberg, L.A. (1996) Elevation of plasma thioredoxin levels in HIV-infected individuals. Int Immunol, 8, 603-611.
Nordstrand, A., Norgren, M., Ferretti, J.J. & Holm, S.E. (1998) Streptokinase as a mediator of acute post-streptococcal glomerulonephritis in an experimental mouse model. Infect Immun, 66, 315-321.
Nordstrand, A., Norgren, M. & Holm, S.E. (1996) An experimental model for acute poststreptococcal glomerulonephritis in mice. Apmis, 104, 805-816.
Nordstrand, A., Norgren, M. & Holm, S.E. (1999) Pathogenic mechanism of acute post-streptococcal glomerulonephritis. Scand J Infect Dis, 31, 523-537.
Oda, T., Yamakami, K., Omasu, F., Suzuki, S., Miura, S., Sugisaki, T. & Yoshizawa, N. (2005) Glomerular plasmin-like activity in relation to nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. J Am Soc Nephrol, 16, 247-254.
Olive, C. (2007) Progress in M-protein-based subunit vaccines to prevent rheumatic fever and rheumatic heart disease. Curr Opin Mol Ther, 9, 25-34.
Oner, A., Atalay, S., Karademir, S. & Pekuz, O. (1993) Acute poststreptococcal glomerulonephritis followed by acute rheumatic carditis: an unusual case. Pediatr Nephrol, 7, 592-593.
Phillips, G.N., Flicker, P.F., Cohen, C., Manjula, B.N. & Fischetti, V.A. (1981) Streptococcal M protein: alpha-helical coiled-coil structure and arrangement on the cell surface. Proc Natl Acad Sci USA, 78, 4689-4693.
Parra, G., Rodriguez-Iturbe, B., Batsford, S., Vogt, A., Mezzano, S., Olavarria, F., Exeni, R., Laso, M. & Orta, N. (1998) Antibody to streptococcal zymogen in the serum of patients with acute glomerulonephritis: a multicentric study. Kidney Int, 54, 509-517.
Pedreanez, A., Viera, N., Rincon, J. & Mosquera, J. (2006) Increased IL-6 in supernatant of rat mesangial cell cultures treated with erythrogenic toxin type B and its precursor isolated from nephritogenic streptococci. Am J Nephrol, 26, 75–81.
Pockley, A.G. (2002) Heat shock proteins, inflammation, and cardiovascular disease. Circulation, 105, 1012-1017.
Pockley, A.G., Georgiades, A., Thulin, T., de Faire, U. & Frostegard, J. (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension, 42, 235-238.
Poon-King, R., Bannan, J., Viteri, A., Cu, G. & Zabriskie, J.B. (1993) Identification of an extracellular plasmin binding protein from nephritogenic streptococci. J Exp Med, 178, 759-763.
Portig, I., Pankuweit, S. & Maisch, B. (1997) Antibodies against stress proteins in the sera of patients with dilated cardiomyopathy. J Moll Cell Cardiol, 29, 2245-2251.
Powis, G. & Montfort, W.R. (2001) Properties and biological activities of thioredoxins. Annu Rev Pharmacol Toxicol, 41, 261-295.
Rammelkamp, C.H., Jr. & Weaver, R.S. (1953) Acute glomerulonephritis, the significance of the variations in the incidence of the disease. J Clin Invest, 32, 345-358.
Rastaldi, M.P., Ferrario, F., Yang, L., Tunesi, S., Indaco, A., Zou, H. & D'Amico, G. (1996) Adhesion molecules expression in noncrescentic acute post-streptococcal glomerulonephritis. J Am Soc Nephrol, 7, 2419-2427.
Rincon, J., Viera, N.T., Romero, M.J. & Mosquera, J.A. (2003) Increased production of chemotactic cytokines and elevated proliferation and expression of intercellular adhesion molecule-1 in rat mesangial cells treated with erythrogenic toxin type B and its precursor isolated from nephritogenic streptococci. Nephrol Dial Transplant, 18, 1072-1078.
Roberts, S., Kosanke, S., Terrence Dunn, S., Jankelow, D., Duran, C.M. & Cunningham, M.W. (2001) Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium. J Infect Dis, 183, 507-511.
Rodriguez-Iturbe, B., Garcia, R., Rubio, L., Cuenca, L., Treser, G. & Lange, K. (1976) Epidemic glomerulonephritis in Maracaibo. Evidence for progression to chronicity. Clin Nephrol, 5, 197-206.
Rodriguez-Iturbe, B. (2004) Nephritis-associated streptococcal antigens: where are we now? J Am Soc Nephrol, 15, 1961-1962.
Romero, M., Mosquera, J., Novo, E., Fernandez, L. & Parra, G. (1999) Erythrogenic toxin type B and its precursor isolated from nephritogenic streptococci induce leukocyte infiltration in normal rat kidneys. Nephrol Dial Transplant, 14, 1867-1874.
Sandson, J., Hamerman, D., Janis, R. & Rojkind, M. (1968) Immunologic and chemical similarities between the streptococcus and human connective tissue. Trans Assoc Am Physicians, 81, 249-257.
Sargent, S.J., Beachey, E.H., Corbett, C.E. & Dale, J.B. (1987) Sequence of protective epitopes of streptococcal M proteins shared with cardiac sarcolemmal membranes. J Immunol, 139, 1285-1290.
Schenk, H., Vogt, M., Droge, W. & Schulze-Osthoff, K. (1996) Thioredoxin as a potent costimulus of cytokine expression. J Immunol, 156, 765-771.
Schett, G., Redlich, K., Xu, Q., Bizan, P., Groger, M., Tohidast-Akrad, M., Kiener, H., Smolen, J. & Steiner, G. (1998) Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. J Clin Invest, 102, 302-311.
Shikhman, A.R. & Cunningham, M.W. (1994) Immunological mimicry between N-acetyl-beta-D-glucosamine and cytokeratin peptides. Evidence for a microbially driven anti-keratin antibody response. J Immunol, 152, 4375-4387.
Shikhman, A.R., Greenspan, N.S. & Cunningham, M.W. (1993) A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-beta-D-glucosamine. J Immunol, 151, 3902-3913.
Song, C.Y., Chen, W.L., Yang, M.C., Huang, J.P. & Mao, S.J. (2005) Epitope mapping of a monoclonal antibody specific to bovine dry milk: involvement of residues 66-76 of strand D in thermal denatured beta-lactoglobulin. J Biol Chem, 280, 3574-3582.
Srivastava, P. (2002) Roles of heat shock proteins in innate and adaptative immunity. Nature Rev Immunol, 2, 185–194.
Tart, A.H., Walker, M.J. & Musser, J.M. (2007) New understanding of the group A Streptococcus pathogenesis cycle. Trends Microbiol, 15, 318-325.
Tontsch, D., Pankuweit, S. & Maisch, B. (2000) Autoantibodies in the sera of patients with rheumatic heart disease: characterization of myocardial antigens by two-dimensional immunoblotting and N-terminal sequence analysis. Clin Exp Immunol, 121, 270-274.
Trouw, L.A., Seelen, M.A. & Daha, M.R. (2003) Complement and renal disease. Mol Immunol, 40, 125-134.
Viera, N., Pedreanez, A., Rincon, J. & Mosquera, J. (2007) Streptococcal exotoxin B increases interleukin-6, tumor necrosis factor alpha, interleukin-8 and transforming growth factor beta-1 in leukocytes. Pediatr Nephrol, 22, 1273-1281.
Wakasugi, N., Tagaya, Y., Wakasugi, H., Mitsui, A., Maeda, M., Yodoi, J. & Tursz, T. (1990) Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2. Proc Natl Acad Sci USA, 87, 8282-8286.
Wright, B.H., Corton, J.M., El-Nahas, A.M., Wood, R.F. & Pockley, A.G. (2000) Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels, 15, 18-22.
Yamakami, K., Yoshizawa, N., Wakabayashi, K., Takeuchi, A., Tadakuma, T. & Boyle, M.D. (2000) The potential role for nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. Methods, 21, 185-197.
Yoshizawa, N. (2000) Acute glomerulonephritis. Intern Med, 39, 687-694.
Yoshizawa, N., Yamakami, K., Fujino, M., Oda, T., Tamura, K., Matsumoto, K., Sugisaki, T. & Boyle, M.D. (2004) Nephritis-associated plasmin receptor and acute poststreptococcal glomerulonephritis: characterization of the antigen and associated immune response. J Am Soc Nephrol, 15, 1785-1793.
Yoshida, S., Katoh, T., Tetsuka, T., Uno, K., Matsui, N. & Okamoto, T. (1999) Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. J Immunol, 163, 351-358.
Zabriskie, J.B. & Freimer, E.H. (1966) An immunological relationship between the group. A streptococcus and mammalian muscle. J Exp Med, 124, 661-678.
Zabriskie, J.B., Hsu, K.C. & Seegal, B.C. (1970) Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance. Clin Exp Immunol, 7, 147-159.
Zabriskie, J.B., Utermohlen, V., Read, S.E. & Fischetti, V.A. (1973) Streptococcus-related glomerulonephritis. Kidney Int, 3, 100-104.